The onset of posttraumatic stress disorder (PTSD) is triggered by a life threatening experience, which leaves a lasting trace of fear memory. In PTSD patients memories become largely generalized, so that a similar context generates a robust recall of a traumatic experience, thus severely compromising individual well-being and day-to-day activities. Currently, there is no ideal treatment for PTSD; exposure therapy is partially effective, but many patients do not respond and often relapse after treatment. Brain functions governing treatment outcome are not well characterized. We propose that inter-individual differences in glucocorticoid and endocannabinoid activity are associated with treatment success, and that pharmacological augmentation of endocannabinoid signaling could lead to improved outcome of exposure therapy by enhancing both the strength and generalization of fear extinction memory. Therefore, gaining insight into these neurobiological mechanisms by mean of preclinical studies will be key in the development of novel and personalized pharmacological treatment options.
According to the last World Health Organization (WHO) report (2014) 27% of the adult population had experienced at least one of a series of mental disorders at some time during lifetimes. This represents an enormous human toll of ill health, with a huge economic impact and, more importantly, with significant social implications due to the persistent functional disability associated with such disorders. In this context, health promotion and disease prevention heavily depend upon our ability to unravel etiological mechanisms and mitigate the outcome of events that contribute to the development of mental illness. However, despite the fact that mental illness is considered a relevant and growing problem for our society, the discovery of new therapeutic approaches to prevent the development of psychiatric diseases and/or mitigate their manifestation at adulthood proceeds slowly and without significant innovations. This is most likely due to the limited knowledge of the functional and molecular alterations that underlie the different pathological phenotypes.
The proposed project investigates GC and EC interaction effects on treatment outcome as well as its mechanistic underpinnings in preclinical rodent models. The project is original and relevant. The research question is highly innovative since a link between GC and EC activity and outcome of exposure therapy is virtually unexplored. This study stems from the possibility of recreating in animals the complex elements that may lead to heightened risk for the development of psychiatric illnesses in a temporal frame that will allow the investigation of short and long-term changes, which cannot be achieved in the clinical setting. The investigation of both strength and generalization of extinction memory is a highly unique and novel aspect of this project, but likely of critical importance to extrapolate success of extinction-based exposure therapy to real life situations leading to an important progress which will extend far beyond the current therapeutic options for PTSD. Our project also aims at assessing the potential biomarker value of parameters of the GC and EC systems for fear-related disorders. It will generate knowledge and interest to develop novel personalized approaches in therapy for PTSD patients with fear-related disorders. Moreover, the findings will help to define patient groups that can benefit most from GC- and EC-based drugs and how aberrations in the GC and EC systems determine treatment resistance, and thereby pave the way to test these drugs at the clinic. Our goal is to establish a proof-of-concept: namely, that exogenously administered GC- or EC-based drugs improve exposure therapy outcome.
The multidisciplinary approach of our study, which encompasses behavioral functional and biochemical analyses, will allow a better understanding of the molecular underpinnings of specific dysfunction in PTSD. Moreover, our study has a significant translational value considering that we plan to: i) disclose molecular mechanisms that may allow the identification of at-risk subjects, who may benefit from preventive intervention; ii) identify mechanisms of resilience that may be potentiated in affected individuals; iii) develop novel therapeutic strategies aimed at correcting both the cognitive and emotional dysfunction of PTSD.